Thiourea derivatives of dihydropyridine NPY antagonists

ABSTRACT

A series of antagonists of NPY have been synthesized and are comprised of thiourea linked piperazine and piperidine derivatives of 4-phenyl-1,4-dihydropyridines of Formula 1.where Z is NR7R8 orand X is CH or N.As antagonists of NPY-induced behavior, these compounds are expected to act as effective anorexiant agents in promoting weight loss and treating eating disorders.

CROSS REFERENCE TO RELATED APPLICATION

This non-provisional application claims priority from provisionalapplication U.S. Ser. No. 60/205,995 filed May 19, 2000.

FIELD OF THE INVENTION

The present invention is directed to heterocyclic compounds comprising4-phenyl-1,4-dihydropyridines having piperazine and piperidine moietiesconnected to the 3-position of the phenyl ring through a thiourealinkage. More particularly, the invention is directed to NPY antagonistof thiourea linked derivatives of 4-phenyl-1,4-dihydropyridine.

BACKGROUND OF THE INVENTION

Neuropeptide Y (NPY) is a 36 amino acid peptide first isolated in 1982from porcine brain. The peptide is a member of a larger peptide familywhich also includes peptide YY (PYY), pancreatic peptide (PP), and thenon-mammalian fish pancreatic peptide Y (PY). Neuropeptide Y is veryhighly conserved in a variety of animal, reptile and fish species. It isfound in many central and peripheral sympathetic neutrons and is themost abundant peptide observed in the mammalian brain. In the brain, NPYis found most abundantly in limbic regions. The peptide has been foundto elicit a number of physiological responses including appetitestimulation, anxiolysis, hypertension, and the regulation of coronarytone.

Structure-activity studies with a variety of peptide analogs (fragments,alanine replacements, point mutations, and internal deletion/cyclizedderivatives) suggest a number of receptor subtypes exist for NPY. Thesecurrently include the Y₁, Y₂, Y₃, and the Y_(1-like) or Y₄ subtypes.

Although a number of specific peptidic antagonists have been identifiedfor most of the subtypes, few selective non-peptidic antagonists havebeen reported to date. The heterocyclic guanidine derivative He 90481(4) was found to be a weak but competitive antagonist of NPY-inducedCa⁺⁺ entry in HEL cells (pA₂=4.43). The compound was also found to haveα₂-adrenergic and histaminergic activity at this dose range.D-Myo-inositol-1,2,6-triphosphate was reported to be a potent butnon-competitive antagonist to NPY-induced contractions in guinea pigbasilar artery. Similarly, the benextramine-like bisguanidines werereported to displace ³H-NPY in rat brain (IC₅₀, 19 and 18.4 μM) and todisplay functional antagonism in rat femoral artery. The bisguanidinewas shown to be functionally selective for the Y₂ receptor since itantagonized the effect of the NPY₂ agonist NPY₁₃₋₃₆ but had no effect onthe vasoconstrictive activity of the NPY₁ agonist [Leu³¹, Pro³⁴]NPY asdisclosed in J. Med. Chem., 1994, 37, 2242-48, C. Chauraisia, et al.

Compound BIBP 3226, as reported in K. Rudolf, et al., Eur. J.Pharmacol., 1994, 271, R11-R13, displaces I-125 Bolton-Hunter labeledNPY in human neuroblastoma cells (SK-N-MC). BIBP antagonized theNPY-induced increase in intracellular Ca⁺⁺ in SK-N-MG cells as well asantagonizing the NPY-induced pressor response in pithed rat experiments.

In addition to displacing I-125 labeled NPY and PYY in humanneuroblastoma cells, compound SR 120819A, as reported in C.Serradeil-LeGal, et al., FEBS Lett., 1995, 362, 192-A6, also antagonizedNPY-related increases in diastolic blood pressure in an anesthetizedguinea pig model.

Over the past two decades, extensive work has been conducted relating tothe 4-aryl-1,4-dihydropyridine class of compounds. Syntheses ofcompounds in this category have been driven by their pharmacologicalactions involving calcium channels rendering them useful for treatingcardiovascular disorders such as ischemia and hypertension.

Numerous prior patents and publications disclose various dihydropyridinederivatives. One example is U.S. Pat. No. 4,829,076 to Szilagyi, et al.disclosing compounds of formula (1) as calcium antagonists for treatinghypertension.

U.S. Pat. No. 5,635,503 to Poindexter, et al. discloses4-(3-substituted-phenyl)-1,4-dihydropyridine derivatives having NPYantagonist properties. These derivatives conform to structural formula(2).

In (2), B is either a covalent bond or the group—NH—. The symbol Zdenotes hetaryl moieties, examples being homopiperazinyl or piperazine.

U.S. Pat. No. 5,554,621 discloses related derivatives where Z is a fusedring or a spiro-fused nitrogen heterocycle. U.S. Pat. No. 5,668,151 alsodiscloses related derivatives where Z is a piperidinyl ortetrahydropyrindinyl.

The above-noted compounds have been shown to possess antagonistactivity. However, there is a continuing need for dihydropyridinederivatives having improved NPY antagonist activity.

SUMMARY OF THE INVENTION

The present invention is directed to novel dihydropyridine derivativeshaving NPY antagonist activity. More particularly, the invention isdirected to thiourea derivatives of dihydropyridines.

Accordingly, a primary aspect of the invention is to provide thiourealinked piperazine and piperidine derivatives of dihydropyridines havingNPY antagonist activity.

The compounds of the invention are effective in promoting weight lossand treating disorders in a mammal by administering to the mammal ananorexiant effective dose of an active compound of the invention.

A further aspect of the invention is to provide a method of treatingclinical disorders amenable to alleviation by eliciting an NPY Y₁response by administering to a patient an effective amount of a compoundof the invention.

Another aspect of the invention is to provide a pharmaceuticalcomposition for use in promoting weight loss and treating eatingdisorders, where the composition comprises an anorexiant effectiveamount of an active compound of the invention and a pharmaceuticallyacceptable carrier.

The compounds of the invention have the Formula I and itspharmaceutically acceptable acid addition salts or hydrates thereof

wherein

R¹ and R⁴ are independently selected from lower alkyl and CO₂R⁶ where R⁶is lower alkyl;

R² and R³ are independently selected from lower alkyl;

R⁵ is hydrogen or halogen;

n is an integer selected from 1 to 5;

Z is

where X is CH or N;

R⁷ and R⁸ are independently selected from lower alkyl and lower alkanol,R⁹ is hydrogen, lower alkyl, —CO₂R⁶, (CH₂)_(m)R¹⁰, hydroxy, cyano, and—(CH₂)_(m)NR¹¹R¹²;

R¹⁰ is selected from C₃₋₇ cycloalkyl, naphthyl and

R¹³ is selected from hydrogen, lower alkyl, lower alkenyl, C₃₋₇cycloalkyl, lower alkoxy, hydroxy, dialkylamino, phenoxy, amino, NRCOR⁶,CO₂R⁶, NO₂, trifluoromethyl, and phenyl;

m is zero or an integer of 1 to 3; and

R¹¹ and R¹² are independently selected from the group consisting ofhydrogen, alkyl, cycloalkyl, alkylene, phenyl, alkylamino, heterocyclicalkyl, methoxy, cyano, lower alkanol, naphthyl, furfuryl,tetrahydrofurfuryl, thiophene, azetidine, lower alkyl ethers, esters,acetamides and carbamates;

and where

is a heterocyclic amine or imine.

These and other aspects of the invention will become apparent to oneskilled in the art as described in the following detailed description.

Detailed Description of the Invention

The present invention is directed to novel compounds having NPY Y₁antagonist activity and pharmaceutical compositions containing the novelcompounds. The invention is further directed to a method of treatingclinical disorders, such as eating disorders, using the novel compoundsof the invention.

The compounds of the invention have the Formula I

The compounds within the preview of the invention include thepharmaceutically acceptable acid addition salts and/or hydrates of thecompounds of Formula I.

In the Formula I, R¹-R⁵, and Z have the following meanings:

R¹ and R⁴ are independently selected from lower alkyl and CO₂R⁶ where R⁶is lower alkyl. A preferred lower alkyl for R¹ and R⁶ is methyl.

R² and R³ are independently selected from lower alkyl, with methyl beingpreferred.

R⁵ is hydrogen or halogen. The halogen can be F, Cl, Br or I, with thepreferred halogen being F.

n is an integer selected from 1 to 5, with 3 being preferred.

Z is

where X is CH or N;

R⁷ and R⁸ are independently selected from lower alkyl and lower alkanol,R⁹ is hydrogen, lower alkyl, —CO₂R⁶, (CH₂)_(m)R¹⁰, hydroxy, cyano, and—(CH₂)_(m) NR¹¹R¹²;

R¹⁰ is selected from C₃₋₇ cycloalkyl, naphthyl and

R¹³ is selected from hydrogen, lower alkyl, lower alkenyl, C₃₋₇cycloalkyl, lower alkoxy, hydroxy, dialkylamino, phenoxy, amino, NRCOR⁶,CO₂R⁶, NO₂, trifluoromethyl, and phenyl;

m is zero or an integer of 1 to 3; and

R¹¹ and R¹² are independently selected from the group consisting ofhydrogen, alkyl, cycloalkyl, alkylene, phenyl, alkylamino, heterocyclicalkyl, methoxy, cyano, lower alkanol, naphthyl, furfuryl,tetrahydrofurfuryl, thiophene, azetidine, lower alkyl ethers, esters,acetamides and carbamates;

and where

is a heterocyclic amine or imine.

The term “lower” refers to substituents such as alkyl or alkoxy groupsthat contain from one to four carbon atoms. Alkenyl groups generallycontain two to four carbon atoms. In embodiments of the invention, R¹ ispreferably CO₂R⁶ where R⁶ is methyl. R² and R³ are preferably methyl. R⁵is preferably hydrogen or fluorine. R⁹ is preferably methoxy phenyl,phenyl, cyclohexyl, or lower alkyl. In one embodiment of the invention,Z is 4-(3-methoxyphenyl) piperidinyl or 4-phenylpiperidinyl.

The compounds of the present invention can exist as optical isomers andboth the racemic mixtures of these isomers as well as the individualoptical isomers themselves are within the scope of the presentinvention. The racemic mixtures can be separated into their individualisomers through well-known techniques such as the separation of thediastereomeric salts formed with optically active acids, followed byconversion back to the optically active bases.

As indicated, the present invention also pertains to thepharmaceutically acceptable non-toxic salts of these basic compounds.Such salts include those derived from organic and inorganic acids suchas, without limitation, hydrochloric acid, hydrobromic acid, phosphoricacid, sulfuric acid, methanesulfonic acid, acetic acid, dichloroaceticacid, tartaric acid, lactic acid, succinic acid, citric acid, maleicacid, fumaric acid, sorbic acid, aconitic acid, salicyclic acid,phthalic acid, enanthic acid, and the like.

The compounds of the invention can be produced by various processes thatuse variations of the Hantzsch synthetic reaction applied to theappropriate starting materials.

The thiourea derivatives of Formula I are produced by reacting thestarting aniline (II) with the thiodiimizole (III) in tetrahydrofuran toproduce the isothiocyanate (IV) as follows:

The isothothiocyanate (IV) is then reacted with the piperazinealkylamine or piperidine alkylamine (V) to produce the thioureaderivative of Formula I

The alkyl amines, such as the propanamines are produced by knownprocesses. The amines can be produced from the appropriate secondaryamines by conjugate addition to acrylonitrile by refluxing in methanol.Where a secondary amine is charged as a free base, the solvent isremoved in vacuo at this time to afford the desired propanenitrileintermediate without further purification. Where secondary amines areacid (HCl or HBr) salts, the solvent is removed in vacuo, and theresidue is taken up in water and then extracted with CH₂Cl₂. The organicextracts are dried (Na₂SO₄) and the solvent is removed in vacuo toafford the desired propanenitrile intermediates. These compounds arethen taken up in MeOH:30% aq NH₃ (85:15) containing Raney nickel, andhydrogenated at 50 psi for 30 min. The catalyst is then removed byfiltration over Celite, and the solvent is removed in vacuo from thefiltrate. The desired propanamines are then isolated by bulb-to-bulbdistillation.

The reaction proceeds as follows.

a: acrylonitrile, MeOH, Δ. b: H₂, NH₃, Raney Nickel, MeOH.

The alkyl piperazine can be synthesized by N-alkylation of thepiperazine followed by removal of the Boc protecting groups as follows.

α: (Bromomethyl)cyclopropane, K₂CO₃, MeCN, Δ. b: 3N HCl, MeOH.

The Boo protecting group can also be cleaved from the intermediate toproduce the unsubstituted piperazine derivative by known processes.

The compounds of the invention demonstrate binding affinity at NPY Y₁receptors. This pharmacologic activity is assayed in SK-N-MC (humanneuroblastoma) cell membranes using iodine-125-labeled I-PYY as aradioligand. The compounds of Formula I had good binding affinities asevidenced by IC₅₀ values being about 10 μM or less at NPY Y₁ receptors.Preferred compounds have IC₅₀ values less than 100 nM and most preferredcompounds have IC₅₀ values of less than 10 nM.

Pharmacologically, the compounds of Formula I act as selective NPYantagonists at NPY Y₁ receptor sites. As such, the compounds of FormulaI are of value in the treatment of a wide variety of clinical conditionswhich are characterized by the presence of an excess of neuropeptide Y.Thus, the invention provides methods for the treatment or prevention ofa physiological disorder associated with an excess of neuropeptide Y,which method comprises administering to a mammal in need of treatment aneffective amount of a compound of Formula I or a pharmaceuticallyacceptable salt, solvate or prodrug thereof. The term “physiologicaldisorder associated with an excess of neuropeptide Y” encompasses thosedisorders associated with an inappropriate stimulation of neuropeptide Yreceptors, regardless of the actual amount of neuropeptide Y present inthe locale.

These physiological disorders include:

disorders or diseases pertaining to the heart, blood vessels or therenal system, such as vasospasm, heart failure, shock, cardiachypertrophy, increased blood pressure, angina, myocardial infarction,sudden cardiac death, congestive heart failure, arrhythmia, peripheralvascular disease, and abnormal renal conditions such as impaired flow offluid, abnormal mass transport, or renal failure;

conditions related to increased sympathetic nerve activity for example,during or after coronary artery surgery, and operations and surgery inthe gastrointestinal track;

cerebral diseases and diseases related to the central nervous system,such as cerebral infarction, neurodegeneration, epilepsy, stroke, andconditions related to stroke, cerebral vasospasm and hemorrhage,depression, anxiety, schizophrenia, dementia, seizure, and epilepsy;

conditions related to pain or nociception;

diseases related to abnormal gastrointestinal motility and secretion,such as different forms of ileus, urinary incontinence, and Crohn'sdisease;

abnormal drink and food intake disorders, such as obesity, anorexia,bulemia, and metabolic disorders;

diseases related to sexual dysfunction and reproductive disorders suchas benign prostatic hyperplasia and male erectile dysfunction;

conditions or disorders associated with inflammation;

respiratory diseases, such as asthma and conditions related to asthmaand bronchoconstriction;

diseases related to abnormal hormone release, such as leutinizinghormone, growth hormone, insulin and prolactin; and

sleep disturbance and diabetes.

There is evidence that NPY contributes to certain symptoms in thesedisorders, such as, hypertension, eating disorders, anddepression/anxiety, as well as circadian rhythms. Compounds of thisinvention are expected to be useful in treating these disorders as wellas sleep disturbance and diabetes.

Selected compounds are tested further for their ability to block orstimulate NPY-induced feeding in test animals by intraperitonealadministration to the animal prior to inducing feeding behavior withNPY. Taken together, these tests indicate that the compounds of thisinvention would be useful anorexiants and would function as anti-obesityagents with further use in various clinical eating disorders. Thus,another aspect of the invention concerns a process for reducing foodintake in an obese mammal or a mammal with an eating disorder. Theprocess comprises systemic administration to such a mammal of ananorexiant-effective dose of a Formula I compound or a pharmaceuticallyacceptable acid addition salt and/or hydrate thereof.

On the basis of pharmacologic testing, an effective dose givenparenterally could be expected to be in a range of about 0.05 to 1 mg/kgbody weight and if given orally would be expected to be in the range ofabout 1 to 50 mg/kg body weight.

For clinical applications, however, the dosage and dosage regimen mustin each case be carefully adjusted, utilizing sound professionaljudgment and considering the age, weight and condition of the recipient,the route of administration and the nature and gravity of the illness.Generally, the compounds of the instant invention will be administeredin the same manner as for available anorexiant drugs such asDiethylpropion, Mazindol, or Phentermine and the daily oral dose wouldcomprise from about 70 to about 1400 mg, preferably 500 to 1000 mgadministered from 1 to 3 times a day. In some instances, a sufficienttherapeutic effect can be obtained at lower doses while in others,larger doses will be required.

The term systemic administration as used herein refers to oral, buccal,transdermal, rectal, and parenteral (i.e. intramuscular, intravenous,and subcutaneous) routes. Generally, it will be found that when acompound of the present invention is administered orally, which is thepreferred route, a larger quantity of reactive agent is required toproduce the same effect as a smaller quantity given parenterally. Inaccordance with good clinical practice, it is preferred to administerthe instant compounds at a concentration level that will produceeffective anoretic effects without causing any harmful or untoward sideeffects. Similarly, the instant compounds can be administered to treatthe various diseases, conditions, and disorders listed above.

Therapeutically, the compounds of Formula I are generally given aspharmaceutical compositions comprised of an effective anoretic amount ofa compound of Formula I or a pharmaceutically acceptable acid additionsalt thereof and a pharmaceutically acceptable carrier. Pharmaceuticalcompositions for effecting such treatment will contain a major or minoramount, e.g. from 95 to 0.5% of at least one compound of the presentinvention in combination with the pharmaceutical carrier. The carriercomprises one or more solid, semi-solid, or liquid diluent, filler, andformulation adjuvant that is non-toxic, inert and pharmaceuticallyacceptable.

Such pharmaceutical compositions are preferably in dosage unit forms;i.e., physically discrete units containing a predetermined amount of thedrug corresponding to a fraction or multiple of the dose which iscalculated to produce the desired therapeutic response. The dosage unitscan contain 1, 2, 3, 4, or more single doses, or, alternatively,one-half, one-third, or one-fourth of a single dose. A single dosepreferably contains an amount sufficient to produce the desiredtherapeutic effect upon administration at one application of one or moredosage units according to the pre-determined dosage regimen usually awhole, half, third, or quarter of the daily dosage administered once,twice, three, or four times a day. Other therapeutic agents can also bepresent. Pharmaceutical compositions which provide from about 50 to 1000mg of the active ingredient per unit dose are preferred and areconventionally prepared as tablets, lozenges, capsules, powders,transdermal patches, aqueous or oily suspensions, syrups, elixirs, andaqueous solutions. Preferred oral compositions are in the form oftablets or capsules and may contain conventional excipients such asbinding agents (e.g. syrup, acacia, gelatin, sorbitol, tragecanth, orpolyvinylpyrrolidone), fillers (e.g. lactose, sugar, maize-starch,calcium phosphate, sorbitol, or glycine), lubricants (e.g. magnesiumstearate, talc, polyethylene glycol or silica), disintegrants (e.g.starch) and wetting agents (e.g. sodium lauryl sulfate).

Solutions or suspensions of a Formula I compound with conventionalpharmaceutical vehicles are generally employed for parenteralcompositions such as an aqueous solution for intravenous injection or anoily suspension for intramuscular injection. Such compositions havingthe desired clarity, stability and adaptability for parenteral use areobtained by dissolving from 0.1% to 10% by weight of the active compoundin water or a vehicle consisting of a polyhydric aliphatic alcohol suchas glycerin, propylene glycol, and polyethylene glycols or mixturesthereof. The polyethylene glycols consist of a mixture of non-volatile,usually liquid, polyethylene glycols which are soluble in both water andorganic liquids and which have molecular weights from about 200 to 1500.

Description of the Specific Embodiments

The compounds of Formula I were prepared in the following Examples. Allcatalytic hydrogenations were performed with Parr Hydrogenators (ParrInstrument Co.) Bulb-to-bulb distillations were carried out on aKugelrohr apparatus (Aldrich). Solvate removal from solids, when noted,was carried out under vacuum drying overnight in an Abderhalden dryingpistol over refluxing ethanol. All melting points were obtained using aThomas-Hoover melting point apparatus and are corrected. ¹H and ¹³C NMRwere obtained using a Bruker AM-300 NMR spectrometer at 300 and 75.5MHz, respectively. NMR solvents used were deuterochloroform (CDCl₃),methyl-d₆-sulfoxide (DMSO-d₆) and deuterium oxide (D₂O).

General Method for the Synthesis of Thioureas

The thiourea derivatives of Formula I were produced from an equivalentmixture of the isothiocyanate intermediate and amine. The mixture wasstirred at room temperature with a chlorinated solvent, such aschloroform or 1,2-dichloroethane for 2 to 24 hours. The resulting crudemixture was filtered through a short bed of silica gel (type H fromMerck). The filter bed was then washed with a non-polar solvent toremove the less polar impurities. The silica gel was then washedsuccessively with solvents of gradually increasing solvent polarity toobtain the analytically pure thiourea compounds.

The thiourea compounds of Examples 1-10 were produced according to thegeneral method.

EXAMPLE 1 Preparation of 1-4-Dihydro-4-[3-[[[[3-[4-(3-methoxyphenyl))piperidinyl]propyl]amino]carbonothioyl]amino]phenyl]-2,6-dimethyl-3,5-pyridineDicarboxylic Acid, Dimethyl Ester

The compound was collected (99%) as a pale foam: ¹H NMR (DMSO-D₆) δ 9.45(S, 1 h), 8.92 (S, 1 h), 7.66 (BR S, 1 H), 7.1 (m, 4 H), 6.86 (d, 1 H,J=7.5 Hz), 6.8 (m, 3 H), 4.87 (s, 1 H), 3.72 (s, 3 H), 3.54 (s, 6 H),3.47 (m, 2 H), 3.95 (br s, 2 H), 2.34 (br s, 2 H), 2.55 (s, 6 H), 1.94(m, 2 H), 1.8 (m, 7 H); ¹³C NMR (DMSO-d₆) δ 180.0, 167.3, 159.3, 148.3,147.9, 145.9, 129.2, 128.1, 122.7, 120.5, 118.9, 112.4, 111.3, 101.2,55.8, 54.9, 53.7, 50.7, 42.6, 41.9, 38.2, 32.8, 25.7, 18.2. Analysiscalculated for C₃₃H₄₂N₄SO₅·0.47 H₂O: C, 64.42; H, 7.03; N, 9.11. Found:C, 64.41; H 7.16; N, 8.76.

EXAMPLE 2 Preparation of1,4-Dihydro-4-[4-fluoro-3-[[[[3-(4-phenylpiperidinyl)propyl]amino]carbonothioyl]amino]phenyl]-2,6-dimethyl-3,5-pyridineDicarboxylic Acid, Dimethyl Ester

The compound was cooled (98%) as an off-white dry foam: ¹H NMR (DMSO-d₆)δ 9.27 (br s, 1 H), 8.99 (br s, 1 H), 7.96 (br s, 1 H), 7.54 (br s, 1H), 7.33-7.28 (m, 2 H), 7.24-7.16 (m, 3 H), 7.01-6.95 (m, 1 H), 6.68 (brs, 1 H), 6.8 (m, 3 H), 4.87 (s, 1 H), 3.56 (s, 6 H), 3.50 (m, 2 H),3.00-2.95 (br d, 2 H, J=8.0 Hz), 2.4-2.3 (m, 2 H), 2.27 (s, 6 H),2.0-1.9 (m, 2 H), 1.7-1.5 (m, 6 H); ¹³C NMR (DMSO-d₆) δ 180.8, 167.3,150.0, 145.6, 143.6, 137.7, 128.4,128.0, 126.6, 126.7, 125.7, 125.5,124.7, 115.2, 114.9, 101.2, 54.9, 53.1, 50.7, 31.9, 25.0, 20.8, 18.2.Analysis calculated for C₃₂H₃₉FN₄SO₄·1.25 H₂O: C, 62.27; H, 6.78; N,9.08. Found: C, 62.26; H, 6.44; N, 8.72.

EXAMPLE 3 Preparation of1,4-Dihydro-4-[3-[[[[3-(4-phenylpiperldinyl)propyl]amino]carbonothioyl]amino]phenyl]-2,6-dimethyl-3,5-pyridineDicarboxylic Acid, Dimethyl Ester

The compound was collected (99%) as a pale foam: ¹H NMR (DMSO-d₆) δ 9.53(br s, 1 H), 8.93 (s, 1 H), 7.76 (br s, 1 H), 7.3-7.1 (m, 8 H), 6.87 (d,1 H, J=7.5 Hz), 4.77 (s, 1 H), 3.56 (s, 6 H), 3.49 (m, 2 H), 3.95 (br s,2 H), 2.36 (br s, 2 H), 2.34 (br s, 2 H), 2.27 (s, 6 H), 1.94 (m, 2 H),1.8 (m, 5 H); ¹³C NMR (DMSO-d₆) δ 180.0, 167.3, 148.2, 146.2, 145.9,139.1, 128.3, 126.7, 125.9, 122.7, 101.2, 55.9, 53.8, 50.7, 42.7, 41.9,38.3, 33.0, 25.7,18.3. Analysis calculated for C₃₂H₄₀N₄SO₄: C, 66.64; H,6.99; N, 9.71. Found: C, 66.74; H, 7.04; N, 9.62.

EXAMPLE 4 Preparation of1,4-Dihydro-4-[3-[[[[3-(4-methyl-1-piperidinyl)propyl]amino]carbonothioyl]amino]-4-fluorophenyl]-2,6-dimethyl-3,5-pyridineDicarboxylic Acid, Dimethyl Ester

The compound was obtained as a white dried foam (quantitative yield)after removal of solvent; ¹H NMR (DMSO-d₆) δ 9.18 (br s, 1 H), 8.97 (s,1 H), 7.85 (br s, 1 H), 7.51 (d, 1 H, J=6.0 Hz), 7.06 (dd, 1 H, J=6.0Hz), 7.06 (dd, 1 H, J=8.4; 10.2 Hz), 6.93 (s, 1 H), 4.85 (s, 1 H), 3.55(s, 6 H), 3.45 (m, 2 H), 2.80 (m, 2 H), 2.31 (m, 2 H), 2.26 (s, 6 H),1.85 (m, 2 H), 1.66 (m, 2 H), 1.52 (m, 2 H), 1.28 (m, 1 H), 1.03 (m, 2H), 0.85 (d, 3 H, J=6.0 Hz); ¹³C NMR (DMSO-d₆) δ 167.2, 146.0, 143.6,125.6, 115.2, 115.0, 101.2, 55.8, 53.2, 50.7, 45.1, 37.8, 33.6, 30.2,25.5, 21.7, 18.2. Analysis calculated for C₂₇H₃₇FN₄O₄S·0.23 C₂H₄Cl₂: C,59.38; H, 6.88; N, 10.09. Found: C, 59.33; H, 6.96; N, 10.01.

EXAMPLE 5 Preparation of1,4-Dihydro-4-[3-[[[[3-(4-ethyl-1-piperidinyl)propyl]amino]carbonothioyl]amino]-4-fluorophenyl]-2,6-dimethyl-3,5-pyridineDicarboxylic Acid, Dimethyl Ester

A white dried foam was formed (quantitative yield) after removal ofsolvent: ¹H NMR (DMSO-d₆) δ 9.16 (br s, 1 H), 8.96 (s, 1 H), 7.83 (br s,1 H), 7.53 (br s, 1 H), 7.06 (t, 1 H, J=8.7 Hz), 6.93 (s, 1 H), 4.85 (s,1 H), 3.55 (s, 6 H), 3.45 (m, 2 H), 2.81 (m, 2 H), 2.26 (br s, 8 H),1.79 (m, 2 H), 1.66 (m, 2 H), 1.57 (m, 2 H), 1.16 (m, 2 H), 1.03 (m, 3H), 0.83 (t, 3 H, J=7.2 Hz); ¹³C NMR (DMSO-d₆) δ 167.3, 145.9, 143.5,115.2, 115.0, 101.2, 55.8, 53.2, 50.8, 43.0, 37.8, 36.8, 31.1, 28.6,25.4, 18.2, 11.1. Analysis calculated for C₂₈H₃₉FN₄O₄S: C, 61.52; H,7.19; N, 10.25. Found: C, 61/20; H, 7.19; N, 9.88.

EXAMPLE 6 Preparation of1,4-Dihydro-4-[3-[[[[3-(4-propyl-1-piperidinyl)propyl]amino]carbonothioyl]amino]-4-fluorophenyl]-2,6-dimethyl-3,5-pyridineDicarboxylic Acid, Dimethyl Ester

A white dried foam was formed (quantitative yield) after removal ofsolvent: ¹H NMR (DMSO-d₆) δ 9.17 (br s, 1 H), 8.96 (s, 1 H), 7.84 (br s,1 H), 7.51 (d, 1 H, J=6.3 Hz), 7.06 (dd, 1 H, J=5.4, 7.3 Hz), 6.93 (s, 1H), 4.85 (s, 1 H), 3.55 (s, 6 H), 3.45 (m, 2 H), 2.81 (m, 2 H), 2.26 (brs, 8 H), 1.80 (m, 2 H), 1.66 (m, 2 H), 1.56 (m, 2 H), 1.28-1.02 (m, 7H), 0.84 (t, 3 H, J=6.9 Hz); ¹³C NMR (DMSO-d₆) δ 167.3, 145.9, 143.5,125.5, 124.6, 115.2, 115.0,101.2, 55.6, 53.2, 50.8, 42.6, 38.2, 37.8,31.5, 28.6, 25.4, 19.2, 18.1, 14.1. Analysis calculated forC₂₉H₄₁FN₄O₄S·0.13 C₂H₄Cl₂: C, 61.27; H, 7.30; N, 9.77. Found: C, 61.29;H, 7.26; N, 9.65.

EXAMPLE 7 Preparation of1,4-Dihydro-4-[3-[[[[3-[4-1,1-dimethylethyl)-1-piperidinyl]propyl]amino]carbonothioyl]amino]-4-fluorophenyl]-2,6-dimethyl-3,5-pyridineDicarboxylic Acid, Dimethyl Ester

A white dried foam was formed (quantitative yield) after removal ofsolvent: ¹H NMR (DMSO-d₆) δ 9.15 (br s, 1 H), 8.95 (s, 1 H), 7.82 (br s,1 H), 7.55 (br s, 1 H), 7.05 (t, J=8.4 Hz), 6.93 (s, 1 H), 4.85 (s, 1H), 3.55 (s, 6 H), 3.44 (m, 2 H), 2.91 (m, 2 H), 2.26 (br s, 8 H),1.77-1.54 (m, 6 H), 1.17-0.92 (m, 3 H), 0.8 (s, 9 H); ¹³C NMR (DMSO-d₆)δ 167.3, 146.0, 143.5, 115.2, 115.0, 101.3, 54.0, 50.7, 37.7, 31.8,27.1, 26.2, 25.7, 18.2. Analysis calculated for C₃₀H₄₃FN₄O₄S·0.21C₂H₄Cl₂: C, 61.36; H, 7.42; N, 9.41. Found: C, 61.35; H, 7.47; N, 9.34.

EXAMPLE 8 Preparation of1,4-Dihydro-4-[3-[[[[3-[4-(1-methylethyl)-1-piperidinyl]propyl]amino]carbonothioyl]amino]-4-fluorophenyl]-2,6-dimethyl-3,5-pyridineDicarboxylic Acid, Dimethyl Ester

This compound was obtained as a white dried foam (quantitative yield)after removal of solvent: ¹H NMR (DMSO-d₆) δ 9.15 (br s, 1 H), 8.97 (s,1 H), 7.83 (brs, 1 H), 7.50 (d, 1 H, J=5.3 Hz), 7.05 (t, J=8.7 Hz), 6.93(s, 1 H), 4.84 (s, 1 H), 3.55 (s, 6 H), 3.45 (m, 2 H), 2.86 (d, 2 H,J=10.0 Hz), 2.26 (m, 8 H), 1.82 (m, 2 H), 1.66 (m, 2 H), 1.54 (m, 2 H),1.20-0.92 (m, 4 H), 0.8 (d, 6 H, J=6.0 Hz); ¹³C NMR (DMSO-d₆) δ 167.3,145.9, 143.5, 125.5, 115.2, 115.0, 101.2, 53.6, 50.8, 41.7, 37.8, 31.9,28.6, 25.5, 19.7, 18.2. Analysis calculated for C₂₉H₄₁FN₄O₄S·0.18C₂H₄Cl₂: C, 60.95; H, 7.27; N, 9.68. Found: C, 60.93; H, 7.34; N, 9.70.

EXAMPLE 9 Preparation of1,4-Dihydro-4-[4-[[[[3-(4-cyclohexyl-1-piperazinyl)propyl]amino]carbonothioyl]amino]-4-fluorophenyl]-2,6-dimethyl-3,5-pyridineDicarboxylic Acid, Dimethyl Ester

A white dried foam was formed (quantitative yield) after removal ofsolvent: ¹H NMR (DMSO-d₆) δ 9.16 (br s, 1 H), 8.96 (s, 1 H), 7.82 (br s,1 H), 7.55 (d, 1 H, J=6.3 Hz), 7.05 (dd, 1 H, J=8.4; 10.4 Hz), 6.93(brs, 1 H), 4.85 (s, 1 H), 3.56 (s, 6 H), 3.44 (br s, 2 H), 2.49-2.26(m, 16 H), 1.70-1.54 (m, 7 H), 1.20-1.05 (m, 6 H); ¹³C NMR (DMSO-d₆) δ167.2, 146.0, 143.6, 115.2, 101.2, 59.7, 50.7, 48.2, 37.8, 28.3, 25.9,25.4, 20.7, 18.2, 14.0. Analysis calculated for C₃₁H₄₄FN₅O₄S·0.54C₄H₈O₂·0.69 H₂O: C, 60.18; H, 7.57; N, 10.58. Found: C, 60.19; H, 7.35;N, 10.59.

EXAMPLE 10 Preparation of1,4-Dihydro-4-[4-[[[[3-(4-cyclohexyl-1-piperazinyl)propyl]amino]carbonothioyl]amino]phenyl]-2,6-dimethyl-3,5-pyridineDicarboxylic Acid, Dimethyl Ester

A white dried foam was formed (quantitative yield) after removal ofsolvent: ¹H NMR (DMSO-d₆) δ 9.45 (br s, 1 H), 8.93 (s, 1 H), 7.66 (br s,1 H), 7.15 (m, 3 H), 6.86 (d, 1 H, J=7.2 Hz), 4.87 (s, 1 H), 3.56 (s, 6H), 3.45 (m, 2 H), 2.42-2.26 (m, 16 H), 1.71-1.54 (m, 7 H), 1.20-1.07(m, 6 H); ¹³C NMR (DMSO-d₆) δ 180.0, 167.3, 148.3, 145.9, 139.0, 128.1,122.7, 101.2, 62.5, 55.5, 53.1, 50.7, 48.2, 42.5, 38.2, 28.3, 25.8,25.5, 25.2, 18.2. Analysis calculated for C₃₁H₄₅N₅O₄S·0.44 C₄H₈O₂·0.64H₂O: C, 62.05; H, 7.92; N, 11.05. Found: C, 62.04; H, 7.75; N, 11.03.

While various embodiments are disclosed herein, these compounds areintended to be exemplary of the invention. It will be appreciated by oneskilled in the art that other compounds can be prepared withoutdeparting from the scope of the invention as defined in the appendedclaims.

What is claimed is:
 1. A compound of Formula I and its pharmaceuticallyacceptable acid addition salts or hydrates thereof

wherein R¹ and R⁴ are independently selected from lower alkyl and CO₂R⁶where R⁶ is lower alkyl; R² and R³ are independently selected from loweralkyl; R⁵ is hydrogen or halogen; n is an integer selected from 1 to 5:Z is

where X is CH or N; is R⁹ is hydrogen, lower alkyl, —CO₂R⁶,(CH₂)_(m)R¹⁰, hydroxy, cyano, and —(CH₂)_(m)NR¹¹R¹²; R¹⁰ is selectedfrom C₃₋₇ cycloalkyl, naphthyl and

R¹³ is selected from hydrogen, lower alkyl, lower alkenyl, C₃₋₇cycloalkyl, lower alkoxy, hydroxy, dialkylamino, phenoxy, amino, NRCOR⁶,CO₂R⁶, NO₂, trifluoromethyl, and phenyl; m is zero or an integer of 1 to3; R¹¹ and R¹² are independently selected from the group consisting ofhydrogen, alkyl, cycloalkyl, phenyl alkylamino, methoxy, cyano,naphthyl, furfuryl, and tetrahydrofurfuryl.
 2. The compound of claim 1,wherein R¹ and R⁴ are —CO₂R⁶.
 3. The compound of claim 1, wherein n is3.
 4. The compound of claim 1, wherein R⁵ is F.
 5. The compound of claim1, wherein Z is 3-methoxyphenylpiperidinyl.
 6. The compound of claim 1,wherein Z is 4-phenylpiperidinyl.
 7. The compound selected from thegroup consisting of1,4-dihydro-4-[3-[[[[3-[4-(3-methoxyphenyl)piperidinyl]propyl]amino]carbonothioyl]amino]phenyl]-2,6-dimethyl-3,5-pyridinedicarboxylic acid, dimethyl ester,1,4-dihydro-4-[3-[[[[3-(4-phenylpiperidinyl)propyl]amino]carbonothioyl]amino]phenyl]-2,6-dimethyl-3,5-pyridinedicarboxylic acid, dimethyl ester, and1,4-dihydro-4-[4-[[[[3-(4-cyclohexyl-1-piperazinyl)propyl]amino]carbonothioyl]amino]phenyl]-2,6-dimethyl-3,5-pyridinedicarboxylic acid, dimethyl ester.
 8. The compound of claim 1, selectedfrom the group consisting of1,4-dihydro-4-[4-fluoro-3-[[[[3-(4-phenylpiperidinyl)propyl]amino]carbonothioyl]amino]phenyl]-2,6-dimethyl-3,5-pyridinedicarboxylic acid, dimethyl ester,1,4-dihydro-4-[3-[[[[3-(4-methyl-1-piperidinyl)propyl]amino]carbonothioyl]amino]-4-fluorophenyl)-2,6-dimethyl-3,5-pyridinedicarboxylic acid, dimethyl ester,1,4-dihydro-4-[3-[[[[3-(4-ethyl-1-piperidinyl]propyl]amino]carbonothioyl]amino]-4-fluorophenyl]-2,6-dimethyl-3,5-pyridinedicarboxylic acid, dimethyl ester,1,4-dihydro-4-[3-[[[[3-(4-propyl-1-piperidinyl)propyl]amino]carbonothioyl]amino]-4-fluorophenyl]-2,6-dimethyl-3,5-pyridinedicarboxylic acid, dimethyl ester,1,4-dihydro-4-[3-[[[[3-[4-1,1-dimethylethyl)-1-piperidinyl]propyl]amino]carbonothioyl]amino]-4-fluorophenyl]-2,6-dimethyl-3,5-pyridinedicarboxylic acid, dimethyl ester,1,4-dihydro-4-[3-[[[[3-[4-(1-methylethyl)-1-piperidinyl]propyl]amino]carbonothioyl]amino]-4-fluorophenyl]-2,6-dimethyl-3,5-pyridinedicarboxylic acid, dimethyl ester, and1,4-dihydro-4-[4-[[[[3-(4-cyclohexyl-1-piperazinyl)propyl]amino]carbonothioyl]amino]-4-fluorophenyl]-2,6-dimethyl-3,5-pyridinedicarboxylic acid, dimethyl ester.
 9. A method of promoting weight lossand treating eating disorders in a mammal comprising administering to amammalian host an anorexiant effective dose of a compound claimed inclaim
 1. 10. A pharmaceutical composition for use in promoting weightloss and treating eating disorders, the composition comprising ananorexiant effective amount of a compound claimed in claim 1 incombination with a pharmaceutically acceptable carrier.